The present invention relates to therapeutically active derivatives of quinoline, including the pharmaceutically acceptable salts and esters thereof, and their use as alpha-2 antagonists.
Some compounds exhibiting alpha adrenergic activity are well known in the art. Those compounds may be used for the treatment of a wide variety of diseases and conditions of the peripheric system and the central nervous system (CNS).
The alpha adrenergic receptors are divided into alpha-1 and alpha-2 adrenoceptors, each of which are further divided into subtypes. Accordingly, alpha-2 adrenoceptors in humans have been subdivided into three pharmacological subtypes known as alpha-2A, alpha-2B and alpha-2C adrenoceptors. A fourth subtype, alpha-2D, is known in rat, bovine and porcine and it corresponds to alpha-2A in man. These subtypes have a distinct distribution in human and animal tissues. For instance, alpha-2C adrenoceptors are concentrated in the CNS, and they appear to play a role in the modulation of various CNS-mediated behavioural and physiological responses.
Compounds that are non-specific to any of the above-mentioned alpha-2 subtypes, and compounds that are specific to certain alpha-2 subtypes, are already known. For example, atipamezole is a non-specific alpha-2 antagonists. Atipamezole has been described in, for example, EP-A-183 492 (cf. p.13, compound XV) and A. Haapalinna et al., Naunyn-Schimiedeberg""s Arch. Pharmacol. Vol. 356, 1997, p.570-582. U.S. Pat. No. 5,902,807 describes compounds that are selective antagonists for the alpha-2C subtype and may be used in the treatment of mental illnesses, e.g. mental disturbances induced by stress. Such compounds include, for example, MK-912 and BAM-1303. Furthermore, WO-A-99 28300 discloses substituted imidazole derivatives having agonist-like activity for alpha-2B or 2B/2C adrenoceptors. The disclosures of all documents cited above in this paragraph are incorporated by reference herein.
As to the derivatives of quinoline, Medicinskaja parazitologija I parazitarnye bolezni, vol.5, 1991, 55-7 (Mikhailitsyn F. S. et al.) and J. Med. Chem., vol.20(8), 1977, 987-996 (Cain F. C. et al.) describe, for example, acridine derivatives as anticancer and/or antiparasitic agents. In addition, a publication by Adams et al in 1985 (Mol. Pharm. 27, 480-491) reports on the binding of diquinolines, diacridines and a number of monoacridines on rat brain alpha-1-, alpha-2- and beta-adrenoceptors.
An object of the present invention is to provide further antagonists of alpha-2 adrenoceptors that can be used for the treatment of diseases or conditions of the pheripheric or central nervous system where alpha-2 antagonists are indicated to be useful. Accordingly, an object of the present invention is to provide further compounds to be used as alpha-2 antagonist agents in the treatment of mammals, including humans and animals.
Another object of the present invention is to provide further compounds useful as selective alpha-2C antagonist agents for the treatment of various disorders or conditions of the central nervous system where alpha-2C antagonists are indicated to be useful.